5(6)-benzene ring substituted benzimidazole-2-carbamate derivatives having anthelmintic activity

ABSTRACT

Benzene ring substituted benzimidazole-2-carbamate derivatives represented by the formula:   where R is a lower alkyl group having 1 to 4 carbon atoms; and R1 is a fused, bicyclic heterocyclic ring moiety. The R1Ssubstitution is at the 5(6)-position. The compounds are useful as pesticides, particularly as anthelmintic and antifungal agents.

United States Patent 1191 Beard 1451 Aug. 26, 1975 S(6)-BENZENE RINGSUBSTITUTED BENZIMIDAZOLE-Z-CARBAMATE DERIVATIVES HAVING ANTHELMINTICACTIVITY [75] Inventor: Colin C. Beard, Palo Alto. Calif.

[73] Assignee: Syntex (U.S.A.) Inc., Palo Alto,

Calif.

[22] Filed: June 19, I973 {21] Appl. No.: 371,365

Primary Examiner.lohn D. Randolph Attorney, Agent, or Firm.loseph l.Hirsch; William 8. Walker [57] ABSTRACT Benzene ring substitutedbenzimidazole-2-carbamate derivatives represented by the formula:

where R is a lower alkyl group having 1 to 4 carbon atoms; and R is afused, bicyclic heterocyclic ring moiety. The R's-substitution is at the5(6)-position. The compounds are useful as pesticides, particularly asanthelmintic and antifungal agents.

7 Claims, No Drawings (6)-BENZENE RING SUBSTITUTEDBENZIMIDAZOLE-Z-CARBAMATE DERIVATIVES HAVING ANTHELMINTIC ACTIVITY FIELDOF THE INVENTION This invention relates to novel chemical compounds.More particularly. this invention relates to novel anthelminticallyactive benzimidazole-2-carbamatc de rivatives wherein the benzene ringis substituted at the 5(6J-position.

BACKGROUND OF THE INVENTION Anthelmintically activebenzimidazole-2-carbamate derivatives either unsubstituted at the5(6)-position or substituted with different substituents than thosedescribed and claimed herein are known in this art (for example. see US.Pat. Nos. 3.480.642; 3.573.32l; 3.574.845; 3.578.676; and 3.595.870).Related fungicidal compounds are also shown in US. pat. Nos. 2.933.504and 3.Ul(l.968.

SUMMARY OF THE INVENTION The novel benzene ring substitutedbenzimidazole-IZ- carbamate derivatives of the present invention can berepresented by the following formula:

where R is a lower alkyl group having I to 4 carbon atoms; and R is afused. bicyclic heterocyelic ring moiety having 5 or 6 atoms in eachring. the rings having 2 common atoms one of which is a nitrogen atom.and the other of which is a carbon atom. the carbon atom beingcovalently bonded to the nitrogen atom, a hetero sulfur atom in eachring and the sulfur atom between the hcterocyelic ring moiety and thebenzimidazole nucleus. The RS-substitution is at the 5(6)-position.

The hydrogen on the nitrogen at the l-position can be replaced withsubstitucnts which do not adversely affect the anthelmintic and/orantifungal properties of the basic compound. including acyl. carbalkoxy.carbamoyl. alkyl-substituted carbamoyl. etc.. substitucnts. As used inthis specification and claims. the term lower alkyl refers to bothstraight and branched chain alkyl groups having a total of from 1through 4 carbon atoms. and thus includes methyl. ethyl. npropyl.isopropyl. n butyl. isobutyl. and t-butyl. The term fused. bicyclichetcrocyclic ring refers to both unsubstituted and substitutedheterocyclic ring moieties hzning 5 or 6 atoms in each ring. the ringshaving 2 common atoms. one of which is a nitrogen atom. and the other ofwhich is a carbon atom. the carbon atom being covalently bonded to thenitrogen atom. a hetero sulfur atom in each ring and the sulfur atombetween the hetcrocyclic ring moiety and the benzimidazole nucleus. andincludes both saturated and unsaturated heterocyclic rings. Exemplaryfused. bicyclic heterocyclic rings expressed in radical form include.for example. 2.3.5.o-tetrahydro-thiazolol 2.3-blthiazol-7a-yl; 2.3dihydro-thiazolo[ 2,3-blthiazol-7a-yl; thiazolo l2.3-b]- thiazol-7a-yl;2.3.5.fi-tetrahydrothiazolol2.3b]-(1.3)- thiazin-Sa-yl;2.3.6.7-tetrahydro-( l.3)thiazino[2.3-b]- (l.3)-thiazin-9 a-yl; and thelike. The aforementioned fused. bicyclic heterocyclic ring can besubstituted with one or more alkyl. such as methyl; aryl. such asphenyl; alkoxy. such as methoxy; or hydroxy radicals. The termcyeloalkyl" refers to cyclic hydrocarbon group having from 3 to 7 carbonatoms including, for example, cyclopropyl. cyclopentyl, cyclohexyl. andthe like. The term alkoxy refers to the group having the formulae ROwherein R is a lower alkyl. as defined above. and in cludes. forexample, methoxy. ethoxy. propoxy. tbutoxy. and the like. The term halorefers to iodo. bromo. chloro. and fluoro radicals. The term acyl" refers to acyl groups derived from carboxylic acids having from I to 6carbon atoms. such as. for example. acetyl. propionyl. butyryl. valeryl.isovaleryl. hcxanoyl. and the like.

Thus. the compounds of the present invention in elude those having thefollowing formula:

N l H where R is as defined above; and X and Y are independently CC.C=C. -CCC. CC=C. or C=CC-. or the substituted counterparts thereof. setforth above.

The compounds of the present invention. and the nontoxic salts thereofformed with pharmaccutically acceptable inorganic or organic acids.possess activity against parasites in mammals. including both mature andimmature parasitic forms. In particular. these compounds are found toexhibit high activity against tape worm infections of the intestinaltract of economically important animals. coupled with low systemictoxicity to the host animal. Such infections may be due to tapewormparasites such as Hymenulcpis mum. Dip \l[dium cunium. Taem'uSlgilltlfd. Mu/(ieeps .reri'alis. etc.

The compounds of the present invention are also use ful as antifungalagents. particularly as systemic fungicides for controlling fungaldiseases of plants of economic importance.

Where the compound has a basic moiety. the term nontoxic salts as usedherein refers to those pharma ceutically acceptable salts of thecompounds of this in vention which do not adversely affect theantifungal or anthelmintic properties of the basic compound. such asthose salts conventionally used in the art. Such nontoxic salts include.for example. salts of inorganic acids such as. for example. sulfuric.sulfonic. sulfamic. nitric. phosphoric. hydrochloric acids and the like.and salts of organic acids such as. for example. acetic. citric. lactic.palmitic. tartaric. succinic. maleic. benzoic acids and the like.

The amount ofthe compound to be administered will depend upon the actualcompound utilized. and upon the weight of the animal being treated. Ingeneral. howver, the daily dosage level will usually be between lbOUtmg/kg and 100 mg/kg of body weight of the anmal being treated. Theactive ingredient is adminisered to the animal by mixing it with thediet of the ani nal, as with a feed mix, or formulating it with anonoxic carrier to give anthelmintic compositions. The :arrier may be anorally ingestible container for the acive ingredient such as, forexample, a gelatin capsule. II it may be an excipient of the kindnormally used in nedicaments of this character, including maize starch,erra alba, lactose, sucrose, calcium phosphate, gelatin, tearic acid,agar, pectin or the like. Examples, of suitlblC liquid carriers arepeanut oil, sesame oil and water.

A wide variety of pharmaceutical forms can be em- )loyed in those caseswherein the medicament is not ldmixed with the feed. Thus, if a solidcarrier is used, he compound can be administered in tablet or capsuleorm. If a liquid carrier is used, the medicament may be n the form of asoft gelatin capsule or in a liquid sus- )ension.

The 5(6)-substituted compounds of the present in- 'ention can beprepared from benzene starting comiounds having nitro and amino oraeylamino (for exlmple, acetamido) substituents at adjacent positions onhe benzene nucleus (e.g., the land 2-positions), and l displaceablemoiety, for example, a chloro substiturnt at the 4- or 5-position of thebenzene nucleus (i.e., it what will be the 5(6)-position of thebenzimidazole :ompound to be prepared). Such a benzene Starting naterialis reacted with a heterocyelic mercaptan to give the corresponding 4- or5- fused, bicyclic hetero- :yclicthio benzene derivative. If applicable,the aeyllmino group is converted to an amino group. The nitro group isreduced to an amino group to afiord a benzene lerivative having aminogroups at the land 2- posiion. The 1,2-diamino compound is then reactedwith 1 1,3-bis(alkoxy-carbonyl)-S-alkyl-isothiourea to give hecorresponding 5(6)-fuscd, bicyelicheterocyclicthii-benzimidazole-Z-carbamate compound of the pres- :ntinvention.

The fused, bicyclic heterocyclicthio compounds of Lhe present inventioncan also be prepared by treating 1 suitable starting material having athiocyanato group it the 4- or 5-position with sodium borohydride toform :he corresponding mcreaptide, reacting the mercaptide with anappropriate fused, bieyclic heterocyclic halide ,alt, converting theresultant compound to the corre- ;ponding l,2-diamino-5( 6 )-fused,bicyclie 'ieterocyclicthiobenzene compound, and reacting the uttercompound with a l,3-bis(alkoxy-carbonyll-S- ilkyl-isothiourea to givethe corresponding 5(6)-fused, )icyclic heterocyc]icthiobenzimidazole-2carbamate ierivative.

A suitable starting material is l-acetamido-2 nitro-4-:hiocyanatobenzene which can be prepared according :0 the method of F.Challenger and A. T. Peters, J. Chem. Soc, 1364 1928 Other suitablestarting matcials include. for example, l-amino-2-nitro-4-:hiocyanatobenzene, 2-amino-4-ehloroliitrobenzene, and2-acetamido-4-chlorol iitrobenzene.

Conversion of the thiocyanato group of theicetamido-2-nitro-4-thiocyanatobcnzene (or Lamino-Z-nitro-4-thiocyanatobenzene) starting material to a neterocyclicthiosubstituent can be affected by treatnent of either of the aforementioned4- thiocyanatobenzene starting materials, at room tcm' perature, withsodium borohydride in dimethylformamide for about V4 to about 2 hours,followed by treatment with a fused, bicyclic heterocyclic halide salt,such as, for example, 2,3,5,6-tetrahydrothiazolo-[2,3- b]-thiazoliumchloride, and the like, in dimethylform' amide, dimethylacetamide.quinoline, pyridine, or an alcoholic medium, such as methanol orethanol. This latter reaction is conducted at a temperature from aboutl0C. to about [50C, generally at about room temperature if feasible, forabout to 12 hours using an excess of the halide reactant. The reactionis preferably conducted in dimethylformamide. Alternatively, themereaptide intermediate can be generated with other bases instead ofsodium borohydride.

Conversion of an aeylamino group, for example, an acetamido group, to anamino group can be effected by treating the aeylamino group-containingcompound with a strong base, such as sodium hydroxide. potassiumhydroxide, potassium carbonate, or sodium carbonate in aqueous methanolat about 20C. to about C. for about /4 hour to about 24 hours.

Reduction of the nitro group to an amino group can be effected bytreating a nitro-group containing compound with iron and a ferrous salt,such as ferrous sulfate or ferrous chloride, or zinc powder, in aqueousmethanol or acetic acid at reflux under neutral conditions for about Ito about 20 hours. It is desirable to add the metal powder in distinctportions, as opposed to all at one time.

The diamino compounds resulting from reduction of the nitro group in thestarting compound to an amino group, and, if necessary, conversion ofthe aeylamino group to an amino group, are converted to thecorresponding benzimidazole-2-carbamate compounds by reacting thediamino compound with a l,3-bis(alkoxycarbonyl)-S-alkyl-isothiourea, forexample, 1,3- bis(methoxycarbonyl)-S-methyl-isothiourea or L3-bis(ethoxycarbonyl)-S-methyl-isothiourea, in an aqueous alcoholicmedium, for example, aqueous methanol or aqueous ethanol, at from aboutroom temperature to the reflux temperature of the reaction medium forabout A: to about 6 hours. The reaction medium is preferably made acidicto a pH of about 4-6 with, for example, a sufficient amount (e.g.,l2moles) of acetic acid. About l2 moles, generally about l.l moles, of theisothiourea reactant are utilized per mole of the diamino compound.

When 2-amino-4-chloro-l-nitrobenzene or 2-acetamido-4-chloro-l-nitrobenzene is utilized as a starting material, itcan be 2-3 to the corresponding heterocyclicthio compound, by thereaction thereof with an appropriate hcterocyclic mercaptan, such as4,5-dihydro-2-mercaptothiazole, and the like, in an inert solvent, suchas dimethylformamide, ethanol, or methanol, in the presence of asuitable inorganic base, such as potassium hydroxide, potassiumcarbonate, sodium carbonate, sodium hydroxide or sodium hydride.Typically, this reaction is conducted at a temperature from about 20C.to about l50C. (i.e., to about the reflux temperature of the solventmaterial) for about V2 to about 6 hours, using an excess (2-3 moles) ofthe mercaptan reactant. lf 2-acetamido-4-ehloro-lnitrobenzene isutilized as the starting material, the acetamido group can be convertedto an amino group as described above. With either case, the nitro groupis reduced to an amino group. The resultant 1,2-diamino compound istreated, as described above, to give the corresponding 5(6)-fused,bicyclic heterocycliethiobenzimidazole-2-carbamate compounds of thisinvention.

In each of the process steps, described herein above and below, unlessotherwise indicated, the respective intermediate products are preferablyseparated from the reaction mixture and purified prior to their use asstarting materials for the next step in the process. Such separation andpurification can be effected by any suitable procedure. For example,typical separation procedures include filtration, extraction,evaporation, and typical purification procedures includecrystallization. and both thin-layer and column chromatography. Optimumseparation and isolation procedures can be obtained for any given stepby routine experimentation as will be apparent to those skilled in thisart.

Particular compounds falling within the scope of the present inventioncan be prepared by selecting an appropriate starting material, forexample, from those referred to above, and then selecting particularreaction step or steps. as for example described above, to give thecompound desired. Particular reaction step or steps may be conducted ina different order from that specified above since, in certain instances,the particular sequence of steps may not be critical. For example, theacetamido group of a 1-acetamido-2-nitro-4- thiocyanatobenzene can beconverted to an amino group before the reaction of such compound with aheterocyclic halide salt or the starting material can be reacted withthe heterocyclic halide salt and then the acetamido group converted tothe corresponding amino group. In view of this disclosure, thepreparation of particular compounds, including compounds falling withinthe scope of the present invention but not particularly described in thespecification, and the various sequences of reaction steps which can beutilized to prepare such compounds, will be apparent to those skilled inthis art.

Exemplary of the compounds of the present invention, as represented bythe structural formula above, are the following illustrative compounds:

5(6)-(2,3,5,o-tetrahydrothiazolol2,3-b1thiazol-7aylthio2-carbornethoxyaminobenzimidazole;

5t 6 2,3-dihydrothiazolol 2,3-b ]thiazol-7a-ylthio2'carbomethoxyaminobenzimidazole;

5(6)-(thiazolol2,3-b]thiazol-7a-ylthio)-2earbomethoxyaminobenzimidazole;

S(o) 2,3,5,(a-tetrahydrothiazolol2,3-bI-( l,3)- thiazin-8a-ylthio)-2-carbomethoxyaminoben zimidazole;

5(6 5,6-dihydrothiazolol2,3-b l ,3)-thia2in-8aylthio)-2-carbomethoxyaminobenzimidazole;

5(6)-( 2,3,6,7-tetrahydro( l,3 )thia2ino[2,3-b]( L3)-thiazin-9a-ylthio)-2carbomethoxyaminobem zimidazole;

5( 6 J-( 2,3,5,o-tetrahydrothiazolol 2,3-blthiazol-7aylthio)-2-carboethoxyaminobenzimidazole;

5( 6 J-( 2,3-dihydrothiazolol 2,3-b Ithiazol-7a-ylthio2-carboethoxyaminobcnzimidazole;

5( 6 )-(thiazolo| 2,3-b lthiazol-7a-ylthio)-2-carbocthoxyaminobcnzimidazole;

5(6H2.3,5,o-tetrahydrothiazolol2,3-b]-( l,3thiazin-Sa-ylthio)-2-earhoethoxyaminobenzimidazole;

5( 6 5,6-dihydrothiazolol 2,3-b]-( l,3 )-thiazin-8aylthio )2':arboethoxyaminobenzimidazole;-

5(6)-(2.3.6,7-tetrahydro( l,3)thiazino[2,3-b]-( l.3) thiazin-Ja-ylthioJ-Z-carboethoxyaminobenzimidazole;

5(6)-(2,3,5.6tetrahydrothiazolol2,3-blthiazol-7aylthio)-2-carbopropoxyainobenzimidazole;

5(6)-(2,3-dihydrothiazolo[2,3-b]thiazol7a-ylthio)-2-carbopropoxyaminobenzimidazole;

5(6)-(thiazolol2,3-blthiazol-7a-ylthio)-2-carbopropoxyaminobenzimidazole;

5(6)-(2,3,5,6-tetrahydrothiazolo[2,3-b]-( 1,3)-thiazin-Sa-ylthio)-2-carbopropoxyaminobenzimidazole;

5(6 5,6-dihydrothiazolol2,3-b l-( 1,3)-thiazin-8aylthio)-2-carbopropoxyaminobenzimidazole;

5(6)-(2,3,6,7-tetrahydro( l ,3 )thiazino[2,3-b]-( I ,3thiazin-Qa-ylthioJ-2-carbopropoxyaminobenzimidazole;

5( 6 H 2,3,5 ,6-tetrahydrothiazolo[2,3-b1thiazol-7aylthio)-2-carbobutoxyaminobenzimidazole;

5(6)-( 2,3-dihydrothiazolol2,3-b]thiazol-7a-ylthio)-2-carbobutoxyaminobenzimidazole;

5(6)-(thiazolo[2,3-b]thiazol-7a-ylthio)-2-carbobutoxyaminobenzimidazole;

5(6)-(2,3,5,6-tetrahydrothiazolo[2,3-b]-( l,3thiazin-Sa-ylthio)-2-carbobutoxyaminobenzimidazole;

5( 6)-( 5,6-dihydrothiazolo[ 2,3-bl-( 1,3 )-thiazin-8aylthio)-2-carbobutoxyaminobenzimidazole; and

5( 6 H 2,3,6,7-tetrahydro( 1,3 )thiazinol 2,3-b]-( I ,3thiazin-9a-ylthio)-2-carbobutoxyaminobenzimidazole.

Of the compounds listed above, 5(6)-( 2,3,5,6- tetrahydrothiazolol 2,3-blthiazol-7a-ylthio-2-carbomethoxyaminobenzimidazolc is presentlypreferred because it has shown substantial and quite specific activityagainst Hymenolepis mum at extremely low concentrations. The compoundis, thusly, an anthelmintic agent specifically adapted for treatment oftapeworn infections of the intestinal tract of economically importantanimals.

DESCRIPTION OF SPECIFIC EMBODIMENTS The following specific descriptionis given to enable those skilled in this art to more clearly understandand practice the present invention. It should not be considered as alimitation upon the scope of the invention but merely as beingillustrative and representative thereof.

PREPARATION 1 I G. of S-methyl isothiouronium sulfate in one liter ofwater is cooled to 0C. and 162.5 g. of methylchloroformate added,followed by the addition of a solution of 250 g. of potassium hydroxidein 750 ml. water at 0 to 5C. The crude product is extracted intobenzene, the benzene dried and evaporated, and the residuerecrystallized from methanol. l,3-bis( methoxycarbonyl)- S-methylisothiourea is thus obtained.

In a similar manner, substituting ethylchloroformate,propylchloroformatc and butylchloroformate for the methylchloroformate,l,3-bis(ethoxycarbonyl )-S methyl isothiourca, l,3-bis( propoxycarbonyl)-S methyl isothiourca, and I,3-bis-(butoxycarbonyl)-S- methylisothiourca are, respectively, prepared.

PREPARATION 2 A mixture of l2 g. of thiazolidine-Z-thione, and 16 g. ofl-bromo-3-chloro propane in I00 ml. of acetonitrile is refluxed for 12hours, cooled and the product removed by filtration. Recrystallizationfrom ethanol gives 2,3,5,o-tetrahydrothiazolol2,3-b]-(1,3)- thiaziniumbromide.

PREPARATION 3 A mixture of 66.5 g. of tetrahydro-l,3-thiazin-2- hioneand 83 g. of l-bromo-3-chloropropane in 200 ml. of ethanol is refluxedfor 24 hours. The solvent is emoved under vacuum and the residuetriturated with ther, then acetone. The product is recrystallized fromthanol yielding 2,3,6,7tetrahydro-( 1,3 )-thiazino- 2,3-b]-( l ,3)-thiazinium bromide.

PREPARATION 4 Thiazolol2,3-bl-thiazolium chloride and thiazo-)l2,3-bl-thiazolium bromide are prepared according 3 the procedure ofBradsher et al., Tetrahedron Let :rs No. 22, pp. 1723-l725 (I965) usingchloroacc- Aldehyde or bromoacetaldehyde aeetal, respectively, 1 placeof the haloacetone or the phenacyl halide.

PREPARATIONS 5 and 6 Z-Mercapto-thiazole is reacted with l-bromo-2-hloroethane or l-bromo-3-chloropropane to afford, :spectively,2,3-dihydrothiazolol 2,3-b1thiazolium halle and5,6-dihydrothiazolol2.3-b]-(l,3)-thiazinium alide. Alternatively, thesecompounds can be preared according to Bradsher et al, supra, using chlo-)acetaldehyde or bromoacetaldehyde acetal and the :quisite heterocyelicstarting material.

EXAMPLE I A mixture of l2l g. of 2amino-4-chlorolitrobenzene, 208 g. ofthiazolidine-2-thionc, 242 g. of otassium carbonate and 1 liter ofdimethylformamide stirred at 90 to 100C. for 8 hours, cooled and rownedinto water. The insoluble material is washed 'ith water and a littlemethanol, and then treated with oiling chloroform, cooled, and theproduct filtered ff. Re-treatment with boiling chloroform and a similareatment with boiling methanol gives 2-amino-4-2,3,5,6-tetrahydrothiazolo[ 2,3-bl-thiazoI-7a-yll- 1- itrobenzene.Recrystallization may be effected from :etic acid if desired.

60 G. of 2-amino-4-[2,3,5,6-tetrahydrothiazolo[2,3-l-thiazol-7a-yll-l-nitrobenzene is suspended in 3 li :rs of methanol. 60G. of iron powder and a solution F30 g. of ferrous sulfate in 600 ml. ofwater are added. he mixture is stirred under gentle reflux forapproxiately hours, during which period three further 60 portions ofiron are added, and after which essenally no starting material remains.The mixture is filred and the filtrate is concentrated under vacuum, leresidue is dissolved in a warm mixture of l liter of hanol and 1 literof water, and re-filtered. 40 G. of l,bis-methoxyearbonyl-S-methyl-isothiourea and 15 l. of acetic acid areadded. The mixture is refluxed :ntly for 4 hours, cooled and the productfiltered off id washed with aqueous ethanol, then methanol to afrd S(6)-( 2,3,5,6-tetrahydrothiazolol 2,3-blthiazoli-ylthio)-2-carbomethoxyamino-benzimidazole. Reystallization maybe effected from aqueous acetic 'id if desired.

In a similar manner substituting I,3-bis(ethoxycar- )nyl )-S-methylisothiourea, l,3bis(propoxycarmyl )-S-methyl isothiourea, and l,3-bis(butoxycarmyl )-Smethyl isothiourea for the l,3

s(methoxycarbonyl )-S-mcthyl isothiourea, the correonding 5(6)-[2,3,5,o-tetrahydrothiazolo-l 2,3-b1-iazol-7a-ylthiol-2-carbalkoxyamino-benzimidazole compounds are prepared,where R is ethyl, propyl and butyl, respectively.

EXAMPLE II A solution of 2.37 g. of l-acetamido-2-nitro-4-thiocyanatobenzene in IS ml. dimethylformamide is treated under nitrogenwith 0.38 g. of sodium borohydride at 2030C. After 1 hour, 5 ml. ofacetone is added followed, 1 hour later, by 6 g. of 2,3,5,6-tetrahydrothiazolo-l 2,3-b l-thiazoliumchloride [see Seto et al., Bull.Chem Soc. Japan 36(6), 7304 (1963); Chemical Abstracts 59, 7509(b)]. Themixture is stirred overnight at 2030 (under nitrogen) then treated withwater. The crude product is filtered off and purified byrecrystallization from methanol chloroform with charcoal treatment,yielding lacetamido-2-nitro-4-(2,3,5,-tetrahydrothiazoIe-l2,3-b]tl1iazol-7a-ylthio)benzene.

0.55 G. of the above product is treated with a mixture of 2 ml. of 5 Naqueous sodium hydroxide and 20 ml. of methanol on the steam bath forl5-20 minutes. The mixture is diluted with water and filtered, yieldinglamino-2-nitro-4-(2,3,5,6-tetrahydrothiazolol2,3-blthiazol-7a-ylthio)benzene.This is treated with 0.6 g. of iron powder and 0.3 g. of ferrous sulfatein 25 ml. water, and ml. methanol. The mixture is refluxed for 5 hours,during which time an additional 0.6 g. of iron powder is added, filteredand the filtrate concentrated under vacuum. The residue is dissolved ina mixture of 10 ml. ethanol and 10 ml. water, filtered from traces ofiron residues and treated with 0.32 g. of l,3-bismethoxycarbonylS-methylisothiourea and 0.l ml. acetic acid at reflux for 3 hours to afford5(6)-( 2,3,5,6-tetrahydrothiazolol2,3-blthiazol-7a-ylthio)-2-carbomethoxyaminobenzimidazolewhich is filtered off.

Using the reactants set forth in the last paragraph of Example Iaccording to the procedure of this Example, the corresponding5(6)-[2,3,5,6-tetrahydrothiazolo[ 2,3-bl-thiazol-7a-ylthio]-2-carbalkoxyaminobenzimidazole compounds are prepared where Ris ethyl, propyl or butyl.

EXAMPLE III In a similar manner to the procedure of Example II, using2,3-dihydrothia2olo[2,3-blthiazolium bromide in place of the2,3,5,6-tetrahydrothiazolo[2,3-blthiazolium chloride, the corresponding5(6)-(2,3-dihydrothiazolo[2.3-blthiazoL7a-ylthio)-2-carbalkoxyaminobenzimidazolecompounds are prepared, where R is methyl, ethyl, propyl or butyl.

EXAMPLE IV In a similar manner to the procedure of Example II, usingthiazolol 2,3-b Ithiazolium chloride in place of the2,3,5,b-tetrahydro-thiazolol2,3-b1thiazolium chloride, the corresponding5(6)-(thiazolo[2,3-b]thiazol 7aylthio)-2-carbalkoxyaminobenzimidazolccompounds are prepared, where R is methyl, ethyl, propyl or butyl.

EXAMPLE V In a similar manner to the procedure of Example II, using2,3.5,6-tetrahydrothiazolol2,3-bl-(1.3)- thiazinium bromide in place ofthe 2,3,5,6-tetrahydrothiazolo[ 2,3-bl-thiazolium chloride. thecorresponding 5(6)-(2,3,5,6-tctrahydrothiazolo| 2,3-b]-( l,3)-thiazinium-8a-ylthio)-2-carbalkoxyaminobcnzimidazole compounds areprepared. where R is methyl, ethyl. propyl or butyl.

EXAMPLE VI In a similar manner to the procedure of Example ll. using2.3,o.7-tetrahydro-( 1.3 )-thiazinol2.3-bl-( 1.3)- thiazinium bromide inplace of the 2.3.5.6- tetrahydrothiazolo [2.3-b lthiazoliuin chloride.the corresponding 6 H 2.3.6.7-tetrahyd ro- 1.3 Jthiazino[2,3-bl-( 1.3Jthiazin-9a-ylthio) Z-carbalkoxyaminobenzimidazole compounds areprepared, where R is methyl. ethyl. propyl. or butyl.

EXAMPLE VII in a similar manner to the procedure of Example ll. using5(6)-dihydrothiazolo[2.3-b]-( l.3)-thiazinium bromide in place of the2.3.5 6-tetrahydrothiazolol2,3- blthiazolium chloride the corresponding5(6)-(5,6- dihyclrothiazolol 2.3-b]-( 1,3)-thiazin-8aylthio)-2-carbalkoxyaminobenzimidazole compounds areprepared, where R is methyl. ethyl. propyl or butyl.

In certain of the Examples above. specific reaction sequences have beenextended. in a general sense. to the preparation of other similar andrelated compounds. It should be understood. however. that with respectto any compound which has been prepared by the extension of a specificreaction sequence. it may be necessary or desirable to utilize solvents.reaction media. recrystallization media. reaction times or temperatures.ctc.. other than the ones given in the specific reaction sequence uponwhich such extension is based. Additionally. the specific reactionsequence or manner in which particular compounds are to be prepared willdepend. inter alia. upon the availability of the necessary startingmaterials. or the ease in which the desired starting materials can beprepared, and the reactivity thereof. These variations are deemed to bewithin the skill of those working in this art and will be apparent froma consideration of the particular reactants utilized and/or particularcompound desired to be produced.

While the present invention has been described with reference tospecific embodiments thereof. it should be understood by those skilledin this art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation. material or composition of matter. process.process step or steps, or then-present objective to the spirit of thisinvention without departing from its essential teachings.

What is claimed is:

I. A compound selected from the group of compounds represented by theformula:

where R is a lower alkyl group having l to 4 carbon atoms; R is a fused.bicyclic heterocyclic ring moiety represented by the formula:

where X and y are independently C-C-- or -C=C. said heterocyelie ringmoiety being optionally substituted with one or more alkyl having 1 to 4carbon atoms, phenyl. alkoxy having I to 4 carbon atoms, or hydroxyradicals; R is hydrogen. acyl having I to 6 carbon atoms. carbalkoxyhaving 2 to 7 carbon atoms, carbamoyl. or alkylcarbamoyl wherein thealkyl portion thereof has I to 4 carbon atoms; the R substitution beingat the 5(6)-position of the benzimidazole nucleus; and thepharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein R is methyl.

3. The compound of claim 1 wherein at least one of the member rings ofsaid bicyclic heterocyclic ring moiety is unsaturated.

4. The compound of claim 1 wherein R is 2.35.6- tetrahydrothiazolol2.3-blthiazol-7a-yl.

5. The compound of claim 1 wherein R is 2,3- dihydrothiazolol 2,3b]thiazol-7a-y l.

6. The compound of claim 1 wherein R is thiazolo[ 2- ,3-b ]-thiazol-7a-yl.

7. The compound of claim I wherein said compound is5(6)-(2.3.5.6-tetrahydrothiazolo[2.3-blthiazol-7aylthio )-2-carbomethoxyaminobenzimidazole.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,901,901 Dated August 26, 1975 Inventofls) COLIN c BEARD It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 2, the structural formula at lines 25-31 should appear N S N-COORColumn 4, line 50, "2-3" should read converted Column 10, the partialstructural formula at lines 20-24, should appear SEAL, hteenth Day ofMay 1976 A He: 1:

RUTH c. msoni C. MA llflflling Ulric,

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1. A COMPOUND SELECTED FROM THE GROUP OF COMPOUNDS REPRESENTED BY THEFORMULA:
 2. The compound of claim 1 wherein R is methyl.
 3. The compoundof claim 1 wherein at least one of the member rings of said bicyclicheterocyclic ring moiety is unsaturated.
 4. The compound of claim 1wherein R1 is 2,3,5,6-tetrahydrothiazolo(2,3-b)thiazol-7a-y1.
 5. Thecompound of claim 1 wherein R1 is 2,3-dihydrothiazolo(2,3-b)thiazol-7a-y1.
 6. The compound of claim 1 wherein R1 isthiazolo(2,3-b)-thiazol-7a-y1.
 7. The compound of claim 1 wherein saidcompound is 5(6)-(2,3,5, 6-tetrahydrothiazolo(2,3-b)thiazol-7a-ylthio)-2-carbomethoxyaminobenzimidazole.